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A myriad of pH-sensitive scaffolds has been reported in recent decades. Information on their behaviour in vitro under conditions that mimic the pH changes that occur during tissue regeneration is abundant. Differently, the in vivo demonstration of the advantages of pH-responsive systems in comparison with non-responders is more limited. The in vivo scenario is very complex and the intricate relationship between the host response, the overall pathological conditions of the patient, and the risk of colonization by microorganisms is very difficult to imitate in in vitro tests. This review aims to shed light on how the changes in pH between healthy and damaged states and also during the healing process have been exploited so far to develop polymer-based scaffolds that actively contribute in vivo to the healing process avoiding chronification. The main strategies so far tested to prepare pH-responsive scaffolds rely on (i) changes in ionization of natural polymers, ionizable monomers and clays, (ii) reversible cross-linkers, (iii) coatings, and (iv) production of CO 2 gas. These strategies are analysed in detail in this review with the description of relevant examples of their performance on specific animal models. The versatility of the techniques used to prepare biocompatible and environment-friendly pH-responsive scaffolds that have been implemented in the last decade may pave the way for a successful translation to the clinic. We report here on the most recent advances in pH-responsive polymer-based scaffolds that have been demonstrated in vivo to be suitable for wound and bone healing. pH is a critical variable in the tissue regeneration process, and small changes can speed up or completely stop the process. Although there is still a paucity of information on the performance in the complex in vivo environment, recently reported achievements using scaffolds endowed with pH-responsiveness through ionic natural polymers, ionizable monomers and clays, reversible cross-linkers, coatings, or formation of CO 2 ensure a promising future towards clinical translation. [Display omitted] [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Three-dimensional printing (3DP) has the potential to cause a paradigm shift in the manufacture of pharmaceuticals, enabling personalised medicines to be produced on-demand. To facilitate integration into healthcare, non-destructive characterisation techniques are required to ensure final product quality. Here, the use of process analytical technologies (PAT), including near infrared spectroscopy (NIR) and Raman confocal microscopy, were evaluated on paracetamol-loaded 3D printed cylindrical tablets composed of an acrylic polymer (Eudragit L100-55). Using a portable NIR spectrometer, a calibration model was developed, which predicted successfully drug concentration across the range of 4–40% w/w. The model demonstrated excellent linearity (R2 = 0.996) and accuracy (RMSEP = 0.63%) and results were confirmed with conventional HPLC analysis. The model maintained high accuracy for tablets of a different geometry (torus shapes), a different formulation type (oral films) and when the polymer was changed from acrylic to cellulosic (hypromellose, HPMC). Raman confocal microscopy showed a homogenous drug distribution, with paracetamol predominantly present in the amorphous form as a solid dispersion. Overall, this article is the first to report the use of a rapid ‘point-and-shoot’ approach as a non-destructive quality control method, supporting the integration of 3DP for medicine production into clinical practice. [ABSTRACT FROM AUTHOR]

Three-dimensional printing (3DP) is gaining momentum in the field of pharmaceuticals, offering innovative opportunities for medicine manufacture. Selective laser sintering (SLS) is a novel, high resolution and single-step printing technology that we have recently introduced to the pharmaceutical sciences. The aim of this work was to use SLS 3DP to fabricate printlets (3D printed tablets) with cylindrical, gyroid lattice and bi-layer structures having customisable release characteristics. Paracetamol-loaded constructs from four different pharmaceutical grade polymers including polyethylene oxide, Eudragit (L100-55 and RL) and ethyl cellulose, were created using SLS 3DP. The novel gyroid lattice structure was able to modulate the drug release from all four polymers. This work is the first to demonstrate the feasibility of using SLS to achieve customised drug release properties of several polymers, in a swift, cost-effective manner, avoiding the need to alter the formulation composition. By creating these constructs, it is therefore possible to modify drug release, which in practice, could enable the tailoring of drug performance to the patient simply by changing the 3D design. [ABSTRACT FROM AUTHOR]

Fused deposition modelling (FDM) 3D printing (3DP) is a revolutionary technology with the potential to transform drug product design in both the pre-clinical and clinical arena. The objective of this pilot study was to explore the intestinal behaviour of four different polymer-based devices fabricated using FDM 3DP technology in rats. Small capsular devices of 8.6 mm in length and 2.65 mm in diameter were printed from polyvinyl alcohol-polyethylene glycol graft-copolymer (PVA-PEG copolymer, Kollicoat IR), hydroxypropylcellulose (HPC, Klucel), ethylcellulose (EC, Aqualon N7) and hypromellose acetate succinate (HPMCAS, Aquasolve-LG). A smaller sized device, 3.2 mm in length and 2.65 mm in diameter, was also prepared with HPMCAS to evaluate the cut off size of gastric emptying of solid formulations in rats. The devices were radiolabelled with Fluorodeoxyglucose ( 18 F-FDG) and small animal positron emission tomography/computed tomography (microPET/CT) was used to track the movement and disintegration of the fabricated devices in the rats. The PVA-PEG copolymer and HPC devices disintegrated after 60min following oral administration. The EC structures did not disintegrate in the gastrointestinal tracts of the rats, whereas the HPMCAS-based systems disintegrated after 420 min. Interestingly, it was noted that the devices which remained intact over the course of the study had not emptied from the stomach of the rats. This was also the case with the smaller sized device. In summary, we report for the first time, the use of a microPET/CT imaging technique to evaluate the in vivo behaviour of 3D printed formulations. The manipulation of the 3D printed device design could be used to fabricate dosage forms of varying sizes and geometries with better gastric emptying characteristics suitable for rodent administration. The increased understanding of the capabilities of 3DP in dosage form design could, henceforth, accelerate pre-clinical testing of new drug candidates in animal models. [ABSTRACT FROM AUTHOR]

3D printing (3DP) technologies have been attracting much recent interest as new methods of fabricating medicines and medical devices. Of the many types of 3DP available, stereolithographic (SLA) printing offers the unique advantage of being able to fabricate objects by cross-linking resins to form networked polymer matrices. Because water can be entrapped in these matrices, it is possible in principle to fabricate pre-wetted, drug-loaded hydrogels and devices. Here, SLA printing was used to prepare ibuprofen-loaded hydrogels of cross-linked polyethylene glycol diacrylate. Hydrogels containing up to 30% w/w water, and 10% w/w ibuprofen, were successfully printed. Dissolution profiles showed that drug release rates were dependent on water content, with higher water content hydrogels releasing drug faster. The conclusion is that SLA 3DP offers a new manufacturing route to pharmaceutical hydrogels. [ABSTRACT FROM AUTHOR]

Patient-centric medicine is a derivative term for personalised medicine, whereby the pharmaceutical product provides the best overall benefit by meeting the comprehensive needs of the individual; considering the end-user from the beginning of the formulation design process right through development to an end product is a must. One way in which to obtain personalised medicines, on-site and on-demand is by three-dimensional printing (3DP). The aim of this study was to investigate the influence of the shape, size and colour of different placebo 3D printed tablets (Printlets™) manufactured by fused deposition modelling (FDM) 3DP on end-user acceptability regarding picking and swallowing. Ten different printlet shapes were prepared by 3DP for an open-label, randomised, exploratory pilot study with 50 participants. Participant-reported outcome (PRO) and researcher reported outcome (RRO) were collected after picking and swallowing of selected printlet geometries including sphere, torus, disc, capsule and tilted diamond shapes. The torus printlet received the highest PRO cores for ease of swallowing and ease of picking. Printlets with a similar appearance to conventional formulations (capsule and disc shape) were also found to be easy to swallow and pick which demonstrates that familiarity is a critical acceptability attribute for end-users. RRO scores were in agreement with the PRO scores. The sphere was not perceived to be an appropriate way of administering an oral solid medicine. Smaller printlet sizes were found to be preferable; however it was found that the perception of size was driven by the type of shape. Printlet colour was also found to affect the perception of the end-user. Our study is the first to guide the pharmaceutical industry towards developing patient-centric medicine in different geometries via 3DP. Overall, the highest acceptability scores for torus printlets indicates that FDM 3DP is a promising fabrication technology towards increasing patient acceptability of solid oral medicines. [ABSTRACT FROM AUTHOR]

Selective laser sintering (SLS) 3-dimensional printing is currently used for industrial manufacturing of plastic, metallic and ceramic objects. To date there have been no reports on the use of SLS to fabricate oral drug loaded products; therefore, the aim of this work was to explore the suitability of SLS printing for manufacturing medicines. Two thermoplastic pharmaceutical grade polymers, Kollicoat IR (75% polyvinyl alcohol and 25% polyethylene glycol copolymer) and Eudragit L100-55 (50% methacrylic acid and 50% ethyl acrylate copolymer), with immediate and modified release characteristics respectively, were selected to investigate the versatility of a SLS printer. Each polymer was investigated with three different drug loadings of paracetamol (acetaminophen) (5, 20 and 35%). To aid the sintering process, 3% Candurin ® gold sheen was added to each of the powdered formulations. In total, six solid formulations were successfully printed; the printlets (3D printed tablets) were robust, and no evidence of drug degradation was observed. In biorelevant bicarbonate dissolution media, the Kollicoat formulations showed pH-independent release characteristics, with the release rate dependent on the drug content. In the case of the Eudragit formulations, these showed pH-dependent, modified-release profiles independent of drug loading, with complete release being achieved over 12 h. In conclusion, this work has demonstrated that SLS is a versatile and practical 3D printing technology which can be applied to the pharmaceutical field, thus widening the armamentarium of 3D printing technologies available for the manufacture of modern medicines. [ABSTRACT FROM AUTHOR]

The increasing prevalence of wound infections caused by antibiotic resistant bacteria is an urgent challenge facing modern medicine. To address this issue the expedient use of antimicrobial metals such as zinc, copper and silver were incorporated into an FDA-approved polymer (polycaprolactone – PCL) to produce filaments for 3D printing. These metals have broad-spectrum antimicrobial properties, and moreover, copper and zinc can enhance the wound healing process. 3D scanning was used to construct 3D models of a nose and ear to provide the opportunity to customize shape and size of a wound dressing to an individual patient. Hot melt extrusion was used to extrude pellets obtained by vacuum-drying of solutions of PCL and the different metals in order to manufacture metal-homogeneously-loaded filaments. Wound dressings with different shapes were produced with the filaments containing different concentrations of metals. Release of the metals from the dressings was determined by inductively coupled plasma atomic emission spectroscopy. All the different metal dressings show fast release (up to 24 h) followed by slow release (up to 72 h). The antibacterial efficacy of the wound dressings was tested using a thermal activity monitor system, revealing that silver and copper wound dressings had the most potent bactericidal properties. This study shows that 3D scanning and 3D printing, which are becoming simpler and more affordable, have the potential to offer solutions to produce personalised wound dressings. [ABSTRACT FROM AUTHOR]

The aim of this study was to manufacture 3D printed tablets (printlets) from enteric polymers by single filament fused deposition modeling (FDM) 3D printing (3DP). Hot melt extrusion was used to generate paracetamol-loaded filaments from three different grades of the pharmaceutical excipient hypromellose acetate succinate (HPMCAS), grades LG, MG and HG. One-step 3DP was used to process these filaments into enteric printlets incorporating up to 50% drug loading with two different infill percentages (20 and 100%). X-ray Micro Computed Tomography (Micro-CT) analysis revealed that printlets with 20% infill had cavities in the core compared to 100% infill, and that the density of the 50% drug loading printlets was higher than the equivalent formulations loaded with 5% drug. In biorelevant bicarbonate dissolution media, drug release from the printlets was dependent on the polymer composition, drug loading and the internal structure of the formulations. All HPMCAS-based printlets showed delayed drug release properties, and in the intestinal conditions, drug release was faster from the printlets prepared with polymers with a lower pH-threshold: HPMCAS LG > HPMCAS MG > HPMCAS HG. These results confirm that FDM 3D printing makes it possible not only to manufacture delayed release printlets without the need for an outer enteric coating, but it is also feasible to adapt the release profile in response to the personal characteristics of the patient, realizing the full potential of additive manufacturing in the development of personalised dose medicines. [ABSTRACT FROM AUTHOR]

Fused deposition modeling (FDM) 3–Dimensional (3D) printing is becoming an increasingly important technology in the pharmaceutical sciences, since it allows the manufacture of personalized oral dosage forms by deposition of thin layers of material. Here, a filament extruder was used to obtain filaments of polyvinyl alcohol (PVA) containing paracetamol or caffeine appropriate for 3D printing. The filaments were used to manufacture caplets for oral administration by FDM 3D printing, with the aim of evaluating the effect of the internal structure (micropore volume), drug loading and composition on drug dissolution behaviour. Micropore volume of the caplets was primarily determined by the presence of large pores due to gaps in the printed layers/net while printing, and the porosity of the caplets was 10 fold higher than the porosity of the extruded filament. Dynamic dissolution drug release tests on the caplets in biorelevant bicarbonate media revealed distinctive release profiles, which were dependent on drug solubility and drug loading. Porosity of the caplets did not help to predict the different drug release profiles. This study confirms the potential of 3D printing to fabricate caplets and helps to elucidate which factors influence drug release from this type of new dosage form. [ABSTRACT FROM AUTHOR]

Maple syrup urine disease (MSUD) is a rare metabolic disorder with a worldwide prevalence of 1 in every 185,000 live births. However, certain populations display a significant overexpression of the disorder where incidence is reported to be 1 in every 52,541 new-borns. The first-line therapy for MSUD involves a strict dietary leucine restriction and oral supplementation of isoleucine and valine. The dose administered to patients requires strict tailoring according to age, weight and blood levels. In current clinical practice, however, practitioners still have to prepare extemporaneous formulations due to the lack of suitable oral treatments for MSUD. Herein, we evaluate the first time use of 3D printing in a hospital setting for the preparation of personalised therapies with the aim of improving safety and acceptability to isoleucine supplementation in paediatric patients suffering from MSUD. This investigation was a single-centre, prospective crossover experimental study. Four paediatric patients with MSUD (aged 3–16 years) were treated at the Clinic University Hospital in Santiago de Compostela, Spain which is a MSUD reference hospital in Europe. The primary objective was to evaluate isoleucine blood levels after six months of treatment with two types of formulations; conventional capsules prepared by manual compounding and personalised chewable formulations prepared by automated 3D printing. A secondary investigation was to evaluate patient acceptability of 3D printed formulations prepared with different flavours and colours. Isoleucine blood levels in patients were well controlled using both types of formulations, however, the 3D printed therapy showed mean levels closer to the target value and with less variability (200–400 µM). The 3D printed formulations were well accepted by patients regarding flavour and colour. The study demonstrates for the first time that 3D printing offers a feasible, rapid and automated approach to prepare oral tailored-dose therapies in a hospital setting. 3D printing has shown to be an effective manufacturing technology in producing chewable isoleucine printlets as a treatment of MSUD with good acceptability. [ABSTRACT FROM AUTHOR]